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Improving antioxidant activity and topical efficacy of idebenone

Idebenone, a potent antioxidant with therapeutic potential for neurodegenerative and skin diseases is limited by low oral and topical bioavailability, due to its physico-chemical properties. This study evaluated the effects of loading pyroglutamic acid (PCA) and solid lipid nanocarriers (SLN) onto idebenone. The antioxidant, anti-glycation and hydrating activities were assessed following topical applications of gel formulations.

SLNs shield bioactive compounds from degradation and therefore raise topical bioavailability. Thus, the loading of SLN onto bioactive compounds as drug delivery systems has been widely studied. One such study revealed improved antioxidant activity of IDE when loaded onto SLN, mediated by increased penetrance into the upper skin layers. Furthermore, the inclusion of SLN results in the formation of an occlusive layer, composed of an adhesive film on the skin surface, and reduces transdermal water loss and increases skin hydration. 

The natural moisturising factor (NMF) is one of the many factors that contribute to the maintenance of ideal skin hydration. NMFs are low molecular weight and water-soluble compounds that are found in the corneocytes. Pyroglutamic acid (2-pyrrolidone-5-carboxylic acid, PCA) is a highly hygroscopic compound and a major hydrating factor of NMF. Thus, the treatment of skin disorders that involve highly dehydrated skin, are likely to benefit from supplementing the skin with PCA. 

In this study, a two-step approach was applied to test for any improvements in topical bioavailability and efficacy of idebenone (from Carbosynth) . Firstly, the idebenone (IDE) ester was synthesised with PCA (IDEPCA) to enhance topical bioavailability and antioxidant properties. Secondly, IDEPCA was loaded onto SLN which is known to benefit drug delivery and penetrance into skin. 

The antioxidant properties of the various IDE derivatives were assessed by measuring oxygen-radical absorbance capacity (ORAC) and NO scavenging ability. Comparing the antioxidant properties of IDE and IDEPCA revealed enhanced ORAC by IDEPCA. Loading IDE and IDEPCA into SLN did not show any difference in ORAC, which may be explained by the slow release of the active molecules from SLN, reducing the amount of free antioxidant molecules. A mild increase in antioxidant activity was observed when IDE or IDEPCA was loaded into SLN, in comparison to unloaded SLN. The inherent antioxidant activity of SLN is due to the presence of oleic residues. On the other hand, IDE and IDEPCA in both free form and loaded into SLN, had reduced NO scavenging ability than Trolox, the control standard. Additionally, the formation of advanced glycation end products (AGEs) in response to oxidative stress was assessed, as another measure of antioxidant activity. In comparison to Trolox, IDE and IDEPCA had higher inhibitory effect on the formation of AGEs, which is doubled when loaded into SLN.  

The hydration activity of the different IDE derivatives in gel formulations and topical application was evaluated. IDEPCA loaded into SLN had significantly higher skin hydration than the unloaded forms and free or SLN-loaded IDE.

Overall, loading of IDE and IDEPCA into SLN reduced antioxidant activity, whilst increasing the inhibitory action on AGE formation. Furthermore, IDEPCA SLN gel formulations had greater hydrating effect than IDE SLN. 

For further information, please refer to the original paper: Montenegro et al (2019)


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